The premise of this RO1 is to test a R21-derived hypothesis that inappropriate intrusion of a mitochondrial anchoring protein, Syntaphilin (SNPH), into neuronal dendrites is harmful in Progressive Multiple Sclerosis (MS). Progressive MS refers to the late-phase of MS and currently this disease phase has no treatments. SNPH is normally expressed only in axons. Surprisingly, under support from a R21, we discovered that SNPH intrudes into dendrites of Purkinje cells in the cerebellum and causes excitotoxicity in a rodent model (Shiverer) for Progressive MS (Joshi et al., 2019, Cell Reports, Article In Press 15th October). This discovery suggests that targeting SNPH to block intrusion into dendrites is a novel treatment for Progressive MS. In this follow-up RO1, we will address three important questions raised by our R21 discovery highly relevant to the basic science and clinical aspect of MS. In Aim #1, we will test the hypothesis that the pathology of dendritic SNPH intrusion in the grey matter is de-coupled from the pathology of white matter. We will test this hypothesis by showing that curing white matter pathology in the Shiverer model (by genetically suppressing axonal degeneration and by remyelination therapy) will not prevent the pathology of dendritic SNPH intrusion. In Aim #2, we will test the hypothesis that dendritic SNPH intrusion causes excitotoxicity by biasing the activation of NMDA receptors towards the pro-death, extra-synaptic NMDA receptors. In Aim #3, we will test the hypothesis that the glutamate released by synaptic activity, when it spills over to the extra-synaptic region as exacerbated by dysfunctional glutamate uptake, constitutes an early glutamate signaling cascade that triggers dendritic SNPH intrusion. Conclusion ? SNPH is a key protein that controls mitochondrial movement with multi-faceted effects on neuronal behaviors in health and disease. Since the cloning of SNPH in 2000, the studies of SNPH in neurons have been exclusively in axons. The Novelty of this RO1 is a paradigm shift to pioneer the study of SNPH in dendrites. The Translational Significance is the surprising discovery that dendritic SNPH mediates excitotoxicity in Progressive MS, thereby opening up new insights to treat MS in this incurable late-phase.